The task of combining sensory signals to form a coherent olfactory representation falls mainly on the piriform cortex (PC). Studies have shown that odor identity is represented as select but spatially dispersed neuronal subgroups in the PC. How these ensembles are generated is still a matter of conjecture. A key step to elucidate the mechanisms that establish these codes is to understand how the PC is set up to read and integrate incoming olfactory bulb (OB) signals. These computational capabilities are determined in large part by the functional connections PC neuronal components make with each other. Of particular interest are synaptic connections made by local interneurons onto pyramidal cells, as these circuits have been shown to be important for tuning pyramidal cells to odor-related inputs from the OB. To date, all studies that have examined PC intracortical circuitry have been purely anatomical and as such have not assessed functional synapses. To assay functional inhibitory circuitry, we focally uncaged glutamate over PC interneurons and recorded the resulting evoked inhibitory postsynaptic currents (IPSCs) in pyramidal cells. We then used IPSC charge as our measure for connective strength. This method allowed us to sample a large pool of unique inhibitory connections onto a single and population of pyramidal cells spread over a wide PC area. Because of this technical advantage, we have found, for the first time, a computationally significant spatial organization to PC circuitry. We found that the relative location of an interneuron to a pyramidal cell dictates connective strength. Interneurons located caudal to a pyramidal cell are more likely to inhibit its spike output than interneurons at more rostral regions. Consequently, OB excitatory inputs that activate mostly caudal microcircuits are less likely to elicit spiking in a pyramidal cell than inputs activating mostly rostral microcircuits. In addition, we have found that pyramidal cells in caudal PC regions receive 3-fold greater inhibition than pyramidal cells located in comparatively rostral areas. Thus, the strength of inhibitory connectivity onto a pyramidal cell is not only determined by interneuron location, but also by the location of the pyramidal cell itself along the PC rostro-caudal axis. We hope to further understand the significance of this rostro-caudal asymmetry by elucidating the cellular and circuit basis for such differential inhibition over PC space. PUBLIC HEALTH RELEVANCE: Findings from this proposal will not only reveal fundamental principles involved in cortical olfactory coding, but will also provide significant insight into clinical issues related to neurodegenerative disease. For instance, imaging studies have revealed that schizophrenic patients display significant dysfunctions in cortical regions involved in processing olfactory stimuli (Moberg et al., 1999;Schneider et al., 2007). Severe deficits in olfactory discrimination and recognition are early warning symptoms of patients with Parkinson's disease (Mesholam et al., 1998;Kranick and Duda, 2008). Alzheimer's disease, Huntington's chorea, alcoholic Korsakoff's syndrome, Pick's disease, all have characteristic olfactory dysfunctions and neuropathology (Mesholam et al., 1998). Thus, from a public health standpoint, elucidation of the underpinnings olfactory network coding holds much promise in understanding neurodegenerative disorders.